Method for reducing organic compounds in microreactor by means of hydrides and/or the derivatives thereof

ABSTRACT

The present invention relates to a process for the reduction of aliphatic, aromatic or heterocyclic organic compounds by means of hydrides and/or derivatives thereof.

[0001] The present invention relates to a process for the reduction ofaliphatic, aromatic or heterocyclic organic compounds by means ofhydrides and/or derivatives thereof.

[0002] The reduction of suitable aliphatic, aromatic or heterocyclicorganic compounds by means of hydrides and/or derivatives thereof is aprocess which is carried out very frequently in the chemical industryand whose considerable importance is also reflected in numerouspublications on this subject.

[0003] However, the performance of reductions by means of hydridesand/or derivatives thereof on an industrial scale is accompanied bysafety problems and dangers. Firstly, use is frequently made ofrelatively large amounts of highly toxic chemical substances, which inthemselves already represent a considerable risk to people and theenvironment, and secondly the reaction conditions can in many cases onlybe controlled well with considerable effort. Furthermore, theachievement and maintenance of protective-gas conditions is often verycomplex in industrial-scale reductions of this type.

[0004] The object of the present invention is therefore to provide aprocess for the reduction of aliphatic, aromatic or heterocyclic organiccompounds by means of hydrides and/or derivatives thereof which avoidsthe above-mentioned disadvantages. In particular, It should be possibleto carry out this process in a simple, reproducible manner withincreased safety for humans and the environment and with good yields,the reaction conditions should be very easy to control, and theprotective-gas conditions necessary for carrying out the reaction shouldbe achievable without major technical effort.

[0005] This object is achieved, surprisingly, by the process accordingto the invention for the reduction of aliphatic, aromatic orheterocyclic organic compounds by means of hydrides and/or derivativesthereof, in which at least one organic compound in liquid or dissolvedform is mixed with at least one hydride and/or derivative thereof inliquid or dissolved form in at least one microreactor and reacted for aresidence time, and the reduced organic compound is, if desired,isolated from the reaction mixture.

[0006] Advantage embodiments of the process according to the inventionare claimed in the sub-claims.

[0007] In accordance with the invention, an aliphatic, aromatic orheterocyclic organic compound or a mixture of at least two of thesecompounds is reduced by the claimed process. Preferably, only onealiphatic, aromatic or heterocyclic organic compound is employed in theprocess according to the invention.

[0008] For the purposes of the invention, a microreactor is a reactorhaving a volume of ≦1000 μl in which the liquids and/or solutions areintimately mixed at least once. The volume of the reactor is preferably≦100 μl, particularly preferably ≦50 μl.

[0009] The microreactor is preferably made from thin silicon structuresconnected to one another.

[0010] The microreactor is preferably a miniaturised flow reactor,particularly preferably a static micromixer. The microreactor is veryparticularly preferably a static micromixer as described in the patentapplication having the international publication number WO 96/30113,which is incorporated herein by way of reference and is regarded as partof the disclosure.

[0011] A microreactor of this type has small channels in which liquidsand/or chemical compounds in the form of solutions are mixed with oneanother by means of the kinetic energy of the flowing liquids and/orsolutions.

[0012] The channels of the microreactor preferably have a diameter offrom 10 to 1000 μm, particularly preferably from 20 to 800 μm and veryparticularly preferably from 30 to 400 μm.

[0013] The liquids and/or solutions are preferably pumped into themicroreactor in such a way that they flow through the latter at a flowrate of from 0.01 μl/min to 100 ml/min, particularly preferably from 1μl/min to 1 ml/min.

[0014] In accordance with the invention, the microreactor is preferablyheatable.

[0015] In accordance with the invention, the microreactor is preferablyconnected via an outlet to at least one residence zone, preferably acapillary, particularly preferably a heatable capillary. After mixing inthe microreactor, the liquids and/or solutions are fed into thisresidence zone or capillary in order to extend their residence time.

[0016] For the purposes of the invention, the residence time is the timebetween mixing of the starting materials and work-up of the resultantreaction solution for analysis or isolation of the desired product(s).

[0017] The residence time necessary in the process according to theinvention depends on various parameters, such as, for example, thetemperature or reactivity of the starting materials. It is possible forthe person skilled in the art to match the residence time to thesevarious parameters and thus to achieve an optimum course of thereaction.

[0018] The residence time of the reaction solution in the system usedcomprising at least one microreactor and, if desired, a residence zonecan be adjusted through the choice of the flow rate of the liquidsand/or solutions employed.

[0019] The reaction mixture is likewise preferably passed through two ormore microreactors connected in series. This achieves an extension ofthe residence time, even at an increased flow rate, and the reductionreaction components employed are reacted in such a way that an optimumproduct yield of the desired reduced organic compound(s) is achieved.

[0020] In a further preferred embodiment, the reaction mixture is passedthrough two or more microreactors arranged in parallel in order toincrease the throughput.

[0021] In another preferred embodiment of the process according to theinvention, the number and arrangement of the channels in one or moremicroreactor(s) are varied in such a way that the residence time isextended, likewise resulting in an optimum yield of the desired reducedorganic compound(s) at the same time as an increased flow rate.

[0022] The residence time of the reaction solution in the microreactor,where appropriate in the microreactor and the residence zone, ispreferably <15 hours, particularly preferably <3 hours, veryparticularly preferably <1 hour.

[0023] The process according to the invention can be carried out in avery broad temperature range, which is essentially restricted by theheat resistance of the materials employed for the construction of themicroreactor, any residence zone and further constituents, such as, forexample, connections and seals, and by the physical properties of thesolutions and/or liquids employed. The process according to theinvention is preferably carried out at a temperature of from −100 to+250° C., particularly preferably from −78 to +150° C. and veryparticularly preferably from 0 to +40° C.

[0024] The process according to the invention can be carried out eithercontinuously or batchwise. It is preferably carried out continuously.

[0025] For carrying out the process according to the invention for thereduction of aliphatic, aromatic or heterocyclic organic compounds bymeans of hydrides and/or derivatives thereof, it is necessary for thereduction reaction to be carried out as far as possible in thehomogeneous liquid phase containing no or only very small solidparticles, since otherwise the channels present in the microreactorsbecome blocked.

[0026] The course of the reduction reaction in the process according tothe invention can be followed using various analytical methods known tothe person skilled in the art and if necessary regulated. The course ofthe reaction is preferably followed by chromatography, particularlypreferably by gas chromatography and/or high-pressure liquidchromatography, and if necessary regulated. In this case, control of thereaction is significantly improved in the process according to theinvention compared with known processes.

[0027] After the reaction, the reduced organic compounds are isolated ifdesired. The reduced product(s) is (are) preferably isolated from thereaction mixture after work-up of the reaction mixture, for example byacidification using hydrochloric acid, if desired neutralisation andsubsequent extraction with a suitable solvent. The extraction isparticularly preferably carried out with an organic solvent.

[0028] Aliphatic, aromatic or heterocyclic organic compounds which canbe employed in the process according to the invention are all aliphatic,aromatic or heterocyclic organic compounds which are known to the personskilled in the art as substrates of reductions by means of hydridesand/or derivatives thereof.

[0029] Preferred aliphatic, aromatic or heterocyclic organic compoundsare aliphatic, aromatic or heterocyclic carbonyl compounds, such asaldehydes and ketones, carboxylic acids, carboxylic acid halides,carboxylic acid esters, corresponding thio or seleno analogues of theabove-mentioned compounds, nitrites, halides or azides.

[0030] Aliphatic carbonyl compounds, carboxylic acids, carboxylic acidhalides, carboxylic acid esters, corresponding thio or seleno analoguesof the abovementioned compounds, nitrites, halides or azides which canbe employed are all aliphatic compounds from the above-mentioned classesof substance which are known to the person skilled in the art and whichare suitable as substrate for reductions by means of hydrides and/orderivatives thereof. Straight-chain, branched, saturated and unsaturatedcompounds are also included here.

[0031] Aromatic carbonyl compounds, carboxylic acids, carboxylic acidhalides, carboxylic acid esters, corresponding thio or seleno analoguesof the abovementioned compounds, nitrites, halides or azides which canbe employed are all aromatic compounds from the above-mentioned classesof substance which are known to the person skilled in the art and whichare suitable as substrate for reductions by means of hydrides and/orderivatives thereof. For the purposes of the invention, this alsoincludes compounds and/or derivatives which have a monocyclic and/orpolycyclic homoaromatic basic structure or a corresponding moiety, forexample in the form of substituents.

[0032] Heterocyclic carbonyl compounds, carboxylic acids, carboxylicacid halides, carboxylic acid esters, corresponding thio or selenoanalogues of the abovementioned compounds, nitrites, halides or azideswhich can be employed are all heterocyclic compounds from theabove-mentioned classes of substance which are known to the personskilled in the art and which are suitable as substrate for reductions bymeans of hydrides and/or derivatives thereof and which contain at leastone heteroatom. For the purposes of the invention, heterocycliccompounds also include heterocyclic compounds and/or derivatives thereofwhich have at least one monocyclic and/or polycyclic heterocyclic basicstructure or a corresponding moiety, for example in the form ofsubstituents. The term “heterocyclic” here also includes saturated,unsaturated and heteroaromatic compounds. Heterocyclic basic structuresor moieties particularly preferably include at least one oxygen,nitrogen or sulfur atom.

[0033] Reducing agents which can be employed in the process according tothe invention are all hydrides and/or derivatives thereof which areknown to the person skilled in the art and are suitable for reductionsof aliphatic, aromatic or heterocyclic organic compounds. The hydride orderivative thereof used is preferably at least one compound selectedfrom boron hydrides, aluminium hydrides, tin hydrides and siliconhydrides, derivatives thereof and mixtures of these reducing agents.Preferably, in each case only one hydride or derivative is employed asreducing agent in the process according to the invention.

[0034] For the purposes of the invention, a derivative of a hydride is astructurally analogous compound in which at least one hydrogen atom hasbeen replaced by a radical other than hydrogen, but at least onehydrogen atom is still present.

[0035] The boron hydride or derivative thereof used is preferablylithium borohydride, sodium borohydride, potassium borohydride,rubidinium borohydride, caesium borohydride, zinc borohydride, calciumborohydride, copper borohydride, tetraalkylammonium borohydride,trialkylphosphonium borohydride or triarylphosphonium borohydride, oralkyl, aryl, alkoxy, aryloxy, acyloxy, cyano or heteroaryl derivativesof the borohydrides or a mixture of the above-mentioned compounds. Theborohydride or derivative thereof used is likewise preferably a borane,in particular diborane, or alkyl, aryl, alkoxy, aryloxy, acyloxy orheteroaryl derivatives of the boranes, complexes of the boranes or ofthe above derivatives with amines, phosphines, ethers or sulfides asligands, where the ligands may in each case be identical or different,or a mixture of the abovementioned compounds. The aluminium hydride orderivative thereof employed is preferably alane (AlH₃), complexaluminium hydrides, in particular lithium aluminium hydride, sodiumaluminium hydride, potassium aluminium hydride, or alkyl, aryl, alkoxy,aryloxy or acyloxy derivatives of alane or of the aluminium hydrides,for example Na bis(2-methoxyethoxy)aluminium hydride ordiisobutylaluminium hydride. Preference is likewise given to complexesof alane, of the aluminium hydrides or of the above derivatives withamines, phosphines, ethers or sulfides as ligands, where the ligands mayin each case be identical or different, or a mixture of theabove-mentioned compounds. Preferred silicon hydrides or derivativesthereof include silanes, in particular monosilane, and alkyl, aryl,alkoxy, aryloxy, acyloxy, cyano or heteroaryl derivatives of thesilanes, or a mixture of the above-mentioned compounds. Examples ofpreferred tin hydrides or derivatives thereof include stannanes, inparticular monostannane, and alkyl, aryl, alkoxy, aryloxy, acyloxy,cyano or heteroaryl derivatives of the stannanes, or a mixture of theabove-mentioned compounds.

[0036] Alkenes and alkynes are capable of insertion into the B-H bondsof boranes. Hydrolysis or peroxohydrolysis of the organoboranes formedin these hydroboration reactions results in hydrocarbons or alcohols. Itmust therefore, where appropriate, be taken into account that thesehydroborations can likewise occur in the case of unsaturated compoundswhich are to be reduced in accordance with the invention if boranesand/or derivatives of the boranes are employed as reducing agent.

[0037] Suitable substituents of the hydride derivatives are all alkyl,aryl, alkoxy, aryloxy, acyloxy or heteroaryl substituents which areknown to the person skilled in the art and which can be employed inreductions of aliphatic, aromatic or heterocyclic compounds.

[0038] In the process according to the invention, the molar ratio oforganic compound to hydride and/or derivative thereof employed dependson the reactivity of the organic compounds, hydrides and/or derivativesemployed. The hydride and/or derivative thereof is preferably employedin an excess of >1 or in an equimolar amount with respect to the organiccompound.

[0039] The selectivity of the reaction depends, besides on theconcentration of the reagents employed, on a number of furtherparameters, such as, for example, the temperature, the type of reducingagent used or the residence time. It is possible for the person skilledin the art to match the various parameters to the respective reductionreaction in such a way that the desired reduced product(s) is (are)obtained.

[0040] It is essential for the process according to the invention thatthe organic compounds and reducing agent employed are either themselvesliquid or are in dissolved form. If these compounds are not themselvesalready in liquid form, they must therefore be dissolved in a suitablesolvent before the process according to the invention is carried out.Preferred solvents are aromatic solvents, particularly preferablytoluene, xylenes, ligroin or phenyl ether, straight-chain, branched orcyclic paraffins, particularly preferably pentane, hexane, heptane,octane, cyclopentane, cyclohexane, cycloheptane or cyclooctane, orstraight-chain, branched or cyclic ethers, particularly preferablydiethyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane, ormixtures of these solvents.

[0041] In the process according to the invention, the danger to peopleand the environment due to released chemicals is considerably reducedand thus results in increased safety during handling of hazardousmaterials. The reduction of aliphatic, aromatic or heterocyclic organiccompounds by the process according to the invention furthermore enablesbetter control of the reaction conditions, such as, for example,reaction duration and reaction temperature, than is possible in theconventional processes. The temperature can be selected individually andkept constant in each volume unit of the system. The course of thereaction in the reduction can be regulated very quickly and precisely inthe process according to the invention. Protective-gas conditions can beachieved and maintained very easily. The reduced organic products canthus be obtained in very good and reproducible yields.

[0042] It is also particularly advantageous that the process accordingto the invention can be carried out continuously. This makes it fasterand less expensive compared with conventional processes, and it ispossible to prepare any desired amounts of the reduced organic compoundswithout major measurement and control effort.

[0043] The invention is explained below with reference to an example.This example serves merely to explain the invention and does notrestrict the general inventive idea.

EXAMPLES

[0044] Reduction of Methyl 3-(3-methyl-3H-imidazol-4-yl)acrylate to3-(3-methyl-3H-imidazol-4-yl)prop-2-en-1-ol

[0045] The reduction of methyl 3-(3-methyl-3H-imidazol-4-yl)acrylateusing diisobutylaluminium hydride (DIBAL-H) was carried out in a staticmicromixer (Technical University of Ilmenau, Faculty of MachineConstruction, Dr.-Ing. Norbert Schwesinger, PO Box 100565, D-98684,Ilmenau) having a physical size of 0.8 mm×0.8 mm×0.6 mm and having atotal of 11 mixing stages with a volume of 0.125 μl each. The totalpressure loss was about 1000 Pa.

[0046] The static micromixer was connected via an outlet and an Omnifitmedium-pressure HPLC connector (Omnifit, Great Britain) to a Tefloncapillary having an internal diameter of 0.49 mm and a length of 1.0 m.The reaction was carried out at room temperature.

[0047] A 2 ml disposable injection syringe was filled with a solution of0.84 g (50 mmol) of methyl 3-(3-methyl-3H-imidazol-4-yl)acrylate and 10ml of toluene, and a further 2 ml syringe was filled with a 20% solutionof diisobutylaluminium hydride (DIBAL-H) in hexane. The contents of thetwo syringes were subsequently transferred into the static micromixer bymeans of a metering pump (Harvard Apparatus Inc., Pump 22, South Natick,Mass., USA). Before performance of the reaction, the experimentalarrangement was calibrated with respect to the dependence of theresidence time on the pump flow rate. The residence time was set to 30,15, 7.5 or 3.75 minutes. The reactions were followed with the aid of aHewlett-Packard GC-MS instrument or a Merck Hitachi LaChrom HPLCinstrument.

[0048] The resultant reaction mixture was acidified using 1 N HCl andextracted with ethyl acetate. The organic extract was subsequently driedover magnesium sulfate and freed from solvent under reduced pressure.

1. Process for the reduction of aliphatic, aromatic or heterocyclicorganic compounds by means of hydrides and/or derivatives thereof,characterised in that at least one organic compound in liquid ordissolved form is mixed with at least one hydride and/or derivativethereof in liquid or dissolved form in at least one microreactor andreacted for a residence time, and the reduced organic compound is, ifdesired, isolated from the reaction mixture.
 2. Process according toclaim 1, characterised in that the microreactor is a miniaturised flowreactor.
 3. Process according to claim 1 or 2, characterised in that themicroreactor is a static micromixer.
 4. Process according to one ofclaims 1 to 3, characterised in that the microreactor is connected viaan outlet to a capillary, preferably a heatable capillary.
 5. Processaccording to one of claims 1 to 4, characterised in that the volume ofthe microreactor is <100 μl, preferably <50 μl.
 6. Process according toone of claims 1 to 5, characterised in that the microreactor isheatable.
 7. Process according to one of claims 1 to 6, characterised inthat the microreactor has channels having a diameter of from 10 to 1000μm, preferably from 20 to 800 μm, particularly preferably from 30 to 400μm.
 8. Process according to one of claims 1 to 7, characterised in thatthe reaction mixture flows through the microreactor at a flow rate offrom 0.01 μl/min to 100 ml/min, preferably from 1 μl/min to 1 ml/min. 9.Process according to one of claims 1 to 8, characterised in that theresidence time of the compounds employed in the microreactor, whereappropriate in the microreactor and the capillaries, is <15 hours,preferably <3 hours, particularly preferably <1 hour.
 10. Processaccording to one of claims 1 to 9, characterised in that it is carriedout at a temperature of from −100 to +250° C., preferably from −78 to+150° C., particularly preferably from 0 to +40° C.
 11. Processaccording to one of claims 1 to 10, characterised in that the course ofthe reaction is followed by chromatography, preferably by gaschromatography, and regulated if necessary.
 12. Process according to oneof claims 1 to 11, characterised in that the aliphatic, aromatic orheterocyclic organic compound is an aliphatic, aromatic or heterocycliccarbonyl compound, carboxylic acid, carboxylic acid halide, carboxylicacid ester, a corresponding thio or seleno analogue of theabove-mentioned compounds, nitrite, halide or azide.
 13. Processaccording to one of claims 1 to 12, characterised in that the hydride orderivative thereof used is at least one compound selected from boronhydrides, aluminium hydrides, tin hydrides, silicon hydrides,derivatives thereof and mixtures of these reducing agents.
 14. Processaccording to claim 13, characterised in that the boron hydride orderivative thereof used is lithium borohydride, sodium borohydride,potassium borohydride, rubidium borohydride, caesium borohydride, zincborohydride, calcium borohydride, copper borohydride, tetraalkylammoniumborohydride, trialkylphosphonium borohydride or triarylphosphoniumborohydride, or an alkyl, aryl, alkoxy, aryloxy, acyloxy, cyano orheteroaryl derivative of the borohydrides, or a mixture of theabovementioned compounds.
 15. Process according to claim 13,characterised in that the borohydride or derivative thereof used is aborane, preferably diborane, or an alkyl, aryl, alkoxy, aryloxy, acyloxyor heteroaryl derivative of the boranes, a complex of the boranes or ofthe above derivatives with amines, phosphines, ethers or sulfides asligands, where the ligands may in each case be identical or different,or a mixture of the above-mentioned compounds.
 16. Process according toclaim 13, characterised in that the aluminium hydride used is alane(AlH₃).
 17. Process according to claim 13, characterised in that thealuminium hydride or derivative thereof used is a complex aluminiumhydride, preferably lithium aluminium hydride, sodium aluminium hydride,potassium aluminium hydride, or an alkyl, aryl, alkoxy, aryloxy oracyloxy derivative of the aluminium hydrides, a complex of the aluminiumhydrides or of the above derivatives which amines, phosphines, ethers orsulfides as ligands, where the ligands may in each case be identical ordifferent, or a mixture of the above-mentioned compounds.
 18. Processaccording to claim 13, characterised in that the aluminium hydridederivative used is diisobutylaluminium hydride.
 19. Process according toClam 17, characterised in that the complex aluminium hydride used is Nabis(2-methoxyethoxy)aluminium hydride.
 20. Process according to claim13, characterised in that the silicon hydride or derivative thereof usedis a silane, in particular monosilane, or an alkyl, aryl, alkoxy,aryloxy, acyloxy, cyano or heteroaryl derivative of the silanes, or amixture of the above-mentioned compounds.
 21. Process according to claim13, characterised in that the tin hydride or derivative thereof used isa stannane, in particular monostannane, an alkyl, aryl, alkoxy, aryloxy,acyloxy, cyano or heteroaryl derivative of the stannanes, or a mixtureof the above-mentioned compounds.
 22. Process according to one of claims1 to 21, characterised in that the hydride and/or derivative thereof isemployed in an excess of >1 or in an equimolar amount with respect tothe organic compound.